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FLT-1 blockers, cutting the legs of leukaemia

15.11.2005

Leukaemia is characterised by an uncontrolled growth of abnormal blood cells in the bone marrow (BM). Escape of the cancerous cells to other organs is linked with worst disease prognosis and less susceptibility to therapy, and, as consequence, to understand the mechanism(s) behind such migration is crucial. And now, in an advance online publication of the journal "Blood", a group of researchers has found that FLT-1 - a molecule implicated in blood vessel growth – is necessary for the escape of the leukaemia cells from the BM, suggesting that blocking of this molecule might be used in the treatment of leukemia.

Leukaemia, or cancer of the white blood cells, affects 4 out of 100,000 people worldwide and in the United States alone more than 2,000 children and 27,000 adults are diagnosed with the disease every year. The illness originates from an abnormal multiplication of the cancerous cells in the BM that leaves little no space for normal blood cells to grow resulting in an impaired immune system that, among other problems, is incapable of efficiently fight infection.

It is known that leukaemia development, like it happens with solid tumours, depends on the development of extra blood vessels (a process known as vascularisation), which serve to supply the fast multiplying cancerous cells with nutrients and help rapid cancer expansion and often metastasis formation. Interestingly, it has also been found that molecules involved in vascularisation seem to be capable of act directly on the cancerous cells. One such example is VEGF (Vascular Endothelial Growth Factor) that appears to affect division, survival and migration of cancer cells and consequently cancer growth and dissemination.

FLT-1 or “Vascular endothelial growth factor receptor”, which binds to VEGF, is another molecule involved in vascularisation that has been suggested to have a role in the division and migration of cancer cells. This observation, together with the fact that FLT-1 is produced in high quantities by leukaemia cells, have led Rita Fragoso, Teresa Pereira, Sérgio Dias and colleagues in Portugal and the United States to investigate the role of FLT-1 in this disease.

For that the group of investigators used cells from patients with ALL, the most common childhood leukaemia, and one in which the abnormally proliferating cells are immature blood cells called lymphoblasts. Cells from different ALL patients, which produced distinct amounts of FLT-1, were injected into mice with no blood cells and followed in order to understand how different quantities of this molecule could affect cell fate and disease progression.

What they found was that FLT-1 levels influenced both migration and cell survival, and therefore also disease outcome.

In fact, cells expressing high quantities of FLT-1 were found in the “exit area” of the BM (from where blood cells migrate into the periphery), in the peripheral circulation and also in other organs, such as the spleen and liver. Cells with low or no FLT-1, on the other hand, stayed within the BM where part of them die. As consequence, animals injected with these last cells presented a slower spread of leukaemia and a higher survival rate than animals injected with cells producing high quantities of FLT-1. Further experiments showed that the different patterns of migration were associated with a gradient of VEGF (which binds FLT-1) found throughout the BM.

What these results showed for the first time was that the localisation of different subsets of leukaemia cells within the BM was dependent on their FLT-1 production, and that different localisations affected cell survival and leukemia expansion and consequently also the survival of animals/patients suffering from the disease.

This work has helped to understand better the biology of leukaemia cells within the BM, how they behave and why, and also the importance of what happens within this organ in disease severity and treatment susceptibility. In fact, migration of ALL cells to outside of the BM not only correlates with a more severe disease but also with a worst response to treatment, since these cells will be less accessible to therapy when spread throughout the body than when restricted to a small area.

But what is more important is that, in view of Fragoso, Pereira, Dias and colleagues’ results, FLT-1 blockers appear as a promising new treatment against leukaemia. And if they are used in combination with chemotherapy they will be able – as result of the cells being more readily available to the injected drugs when stopped within the BM- to increase treatment effectiveness what is certainly good news to patients all over the world.

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